Abstract 3804: Enhancement of Sonic Hedgehog-induced Cardiac Functional Recovery is Augmented by CXCR4 Antagonist via MMP-9-dependent Pathway after Myocardial Infarction
Background: We have shown that the Sonic Hedgehog (Shh) embryonic signalling pathway can be reactivated in myocardial infarction (MI) in adults inducing expression of pro-angiogenic factors. We hypothesized that combining Shh gene therapy and endothelial progenitor cell (EPC) mobilization by a CXCR4 antagonist, AMD3100 (AMD), could exert synergistic effects and would be superior to either single strategy for the treatment of MI.
Methods and results: MI was induced in WT and GFP-bone marrow (BM) transplanted mice randomly assigned in 4 treatment groups: control; AMD (single dose 1 hour after onset of MI, 5mg/kg s.c.); Shh (intramyocardial administration of 100μg Shh plasmid DNA at time of MI surgery); AMD+Shh group. Left ventricular ejection fraction (LVEF) was evaluated by echo up to 4 wks post MI. AMD+Shh group exhibited the best LV function (control: 28+/−3%; AMD: 36+/−2%; Shh: 40+/−3%; AMD+Shh: 48+/−2%; P<0.05 AMD+Shh vs. other groups). These results were confirmed by cine MRI up to 6 weeks after MI for EF (P<0.01) and by contrast echo for infarct size (P<0.05). Furthermore, combination of AMD with sub-therapeutic dose of Shh resulted in a significant improvement of cardiac function recovery compared to monotherapy, highlighting its synergistic effect (P<0.05). Elastic staining and immunohistological analyses demonstrated reduced infarct size and increased capillary density in the AMD+Shh group (both P < 0.05). Combination therapy was also associated with significant increase in number of GFP-BS lectin BM-derived cells incorporated into the ischemic area (P<0.05). We then explored the certain potential mechanisms of the favourable effects of combination therapy. MMP-9 mRNA expression was increased in ischemic myocardium in the AMD+Shh (10-fold versus control). The positive effect on EF of combined treatment was attenuated in MMP-9 KO mice (WT mice 49+/−2% vs. KO mice 36+/−4%; P<0.05), suggesting that MMP-9 might be a key modulator of the combination therapy.
Conclusion: Pharmacological enhancement of Shh gene therapy via BM-cell mobilization by a CXCR4 antagonist is mediated via an MMP-9-dependent pathway. The combination may offer advantages in safety and feasibility by allowing lower dose gene transfer while improving outcome post-MI